PROJECT SUMMARY/ABSTRACT Endometriosis is a common and poorly understood disease affecting millions of women around the world. The impact on fertility and pelvic pain is estimated to cost $22 billion dollars, but this does not include the costs to treat IBS, interstitial cystitis and the cost of failed Assisted Reproductive Technology (ART) cycles. It is estimated that 40% of failed ART cycles are due to undiagnosed endometriosis, and most women undertaking ART have never been tested. This proposal is based on established technology that detects all stages of endometriosis. Based on published results, women who over-express the oncogene BCL6 have a 47% reduction in live birth rate compared to women with normal BCL6. This proposal will develop this technology, validate these findings and pursue a less invasive test format. Aims including those in Phase I, which will validate and examine a second co-expressed biomarker, Sirtuin 1 (SIRT1) present in endometriosis cases at all phases of the menstrual cycle in women with documented endometriosis. This first phase will also study expression of SIRT1 and BCL6 in alternative tissue sources including blood, saliva, urine, and cervical mucous using ELISA technology. Aims in Phase II will examine expression of BCL6 and/or SIRT1 as predictors of pregnancy outcomes in at a major IVF center. In women who test positive for SIRT1/BCL6 with suspected endometriosis, a second multi-center study will examine whether suppression of endometriosis with a novel, newly approved GnRH agonist (Elagolix) followed by embryo transfer will improve outcomes. Finally, the team will develop, validate, and commercialize a reference laboratory test for endometriosis and endometrial receptivity using less invasive approaches for measuring SIRT or BCL6 based on Phase I results. The final validation of a reference laboratory test will involve prospective testing before laparoscopy for pelvic pain or infertility (cases and infertile controls) and for women with fertility undergoing tubal ligation for permanent sterilization (fertile controls). With this approach the sensitivity, specificity, and negative and positive predictive value can be defined. The goal for this project is to establish a validated new, less invasive, test for endometriosis by 2021 that will allow all physicians treating women to shorten the time to diagnosis for endometriosis in a variety of clinical settings including pelvic pain, infertility, irritable bowel syndrome and other pelvic complaints.